JP6250564B2 - Method for producing thienopyrimidine derivative - Google Patents

Description

  The present invention relates to a method for producing a thienopyrimidine derivative having a gonadotropin releasing hormone (GnRH) antagonistic action.

(Background of the Invention)
Secretion of anterior pituitary hormones is a peripheral hormone secreted from the target organ of each hormone and a secretion promoting or secreting hormone secreted from the hypothalamus that is the upper center of the anterior pituitary gland (hereinafter referred to as These hormone groups are collectively referred to as hypothalamic hormones.) To date, nine types of hypothalamic hormones, such as thyroid stimulating hormone releasing hormone (TRH) or gonadotropin releasing hormone (GnRH: also called LH-RH (luteinizing hormone releasing hormone)) have been confirmed. . The gonadotropin-releasing hormone antagonist inhibits the binding of LH-RH to the LH-RH receptor in the anterior pituitary gland and induces luteinizing hormone (LH) / follicle stimulating hormone (LH) from the anterior pituitary gland ( By suppressing the secretion of FSH), the effects of LH / FSH on the ovary are suppressed, and the blood hormone levels that cause endometriosis / uterine fibroids are reduced, thereby reducing the effects on these diseases. Is expected.
As thienopyrimidine derivatives having gonadotropin-releasing hormone antagonistic activity and methods for producing the same, for example, thienopyrimidine derivatives and methods for producing them described in Patent Documents 1 and 2 and Non-Patent Document 1 are known.

WO00 / 56739 WO2004 / 067535

J. et al. Med. Chem. 2011, 54, 4998-5012.

  Development of a production method for safely obtaining a thienopyrimidine derivative or a salt thereof having a high-yield and high-quality (eg, high-purity) gonadotropin-releasing hormone antagonistic activity is desired.

As a result of diligent research to solve the above-mentioned problems, the present inventor has achieved high yield and high quality 1- {4- [1- (2,6-difluorobenzyl)-by using the production method of the present invention. 5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} It has been found that -3-methoxyurea or a salt thereof can be obtained more safely, and the present invention has been completed.
That is, the present invention is:
[1] 6- (4-Aminophenyl) -1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) thieno [2,3-d] pyrimidine -1,4- (1-H, 3H) -dione or a salt thereof, 1,1'-carbonyldiimidazole or a salt thereof and methoxyamine or a salt thereof are reacted, 2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] A process for producing pyrimidin-6-yl] phenyl} -3-methoxyurea or a salt thereof;
[2] 6- (4-Aminophenyl) -1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) thieno [2,3-d] pyrimidine 1.6 to 2.5 equivalents of 1,1′-carbonyldiimidazole or a salt thereof and 1,1′-carbonyldiimidazole or a salt thereof relative to 2,4 (1H, 3H) -dione or a salt thereof 1.0 to 1.5 equivalents of methoxyamine or a salt thereof with respect to
The production method according to the above [1];
[2A] 6- (4-Aminophenyl) -1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) thieno [2,3-d] pyrimidine -2,4 (1H, 3H) -dione or a salt thereof, 1,1'-carbonyldiimidazole or a salt thereof and methoxyamine or a salt thereof are reacted, and then a reaction mixture (reaction solution) or a reaction mixture (reaction solution) 1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2 , 3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea or a salt thereof, characterized by adding tetrahydrofuran,
1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2,3,4- A process for producing tetrahydrofuran solvate crystals of tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea or a salt thereof;
[3] 1- {4- [1- (2,6-Difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2,3 , 4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea or a tetrahydrofuran solvate crystal thereof, dimethylsulfoxide, dimethylformamide (N, N′-dimethylformamide. An alkyl alcohol and one selected from the group consisting of dimethylacetamide (sometimes referred to herein as DMF) and dimethylacetamide (N, N′-dimethylacetamide; sometimes referred to herein as DMAc). Characterized by recrystallization,
1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2,3,4- A process for producing crystals of tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea or a salt thereof;
[4] 2-[(2,6-difluorobenzyl) ethoxycarbonylamino] -4-dimethylaminomethyl-5- (4-nitrophenyl) thiophene-3-carboxylic acid in the presence of propylphosphonic anhydride and base Reacting an acid or a salt thereof with 3-amino-6-methoxypyridazine or a salt thereof,
Of ethyl (2,6-difluorobenzyl)-[4-dimethylaminomethyl-3- (6-methoxypyridazin-3-ylcarbamoyl) -5- (4-nitrophenyl) thiophen-2-yl] carbamate or a salt thereof Production method;
[5] 2-[(2,6-difluorobenzyl) ethoxycarbonylamino] -4-dimethylaminomethyl-5- (4-nitrophenyl) thiophene-3-carboxylic acid in the presence of propylphosphonic anhydride and base Reacting an acid or a salt thereof with 3-amino-6-methoxypyridazine or a salt thereof;
The resulting ethyl (2,6-difluorobenzyl)-[4-dimethylaminomethyl-3- (6-methoxypyridazin-3-ylcarbamoyl) -5- (4-nitrophenyl) thiophen-2-yl] carbamate or its Subjecting the salt to a cyclization reaction,
1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -6- (4-nitrophenyl) thieno [2,3-d] pyrimidine- obtained 2,4 (1H, 3H) -dione or a salt thereof is subjected to a reduction reaction,
6- (4-aminophenyl) -1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) thieno [2,3-d] pyrimidine- obtained 2,4 (1H, 3H) -dione or a salt thereof is reacted with 1,1′-carbonyldiimidazole or a salt thereof and methoxyamine or a salt thereof,
1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2,3,4- A process for producing tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea or a salt thereof;
[6] Ethyl 2-[(2,6-difluorobenzyl) ethoxycarbonylamino] -4-methyl-5 in the presence of 2,2′-azobis (2,4-dimethylvaleronitrile) and trifluoromethylbenzene -(4-nitrophenyl) thiophene-3-carboxylate or a salt thereof and N-bromosuccinimide are reacted,
A process for producing ethyl 4-bromomethyl-2-[(2,6-difluorobenzyl) ethoxycarbonylamino] -5- (4-nitrophenyl) thiophene-3-carboxylate or a salt thereof;
[7] Ethyl 2-[(2,6-difluorobenzyl) ethoxycarbonylamino] -4-methyl-5 in the presence of 2,2′-azobis (2,4-dimethylvaleronitrile) and trifluoromethylbenzene Reacting-(4-nitrophenyl) thiophene-3-carboxylate or a salt thereof with N-bromosuccinimide;
The resulting ethyl 4-bromomethyl-2-[(2,6-difluorobenzyl) ethoxycarbonylamino] -5- (4-nitrophenyl) thiophene-3-carboxylate or a salt thereof is reacted with dimethylamine or a salt thereof. ,
The resulting ethyl 2-[(2,6-difluorobenzyl) ethoxycarbonylamino] -4-dimethylaminomethyl-5- (4-nitrophenyl) thiophene-3-carboxylate is subjected to hydrolysis,
2-[(2,6-difluorobenzyl) ethoxycarbonylamino] -4-dimethylaminomethyl-5- (4-nitrophenyl) thiophene-3-carboxylic acid or a salt thereof obtained and 3-amino-6-methoxy Reacting pyridazine or a salt thereof in the presence of propylphosphonic anhydride and a base;
The resulting ethyl (2,6-difluorobenzyl)-[4-dimethylaminomethyl-3- (6-methoxypyridazin-3-ylcarbamoyl) -5- (4-nitrophenyl) thiophen-2-yl] carbamate or its Subjecting the salt to a cyclization reaction,
1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -6- (4-nitrophenyl) thieno [2,3-d] pyrimidine- obtained 2,4 (1H, 3H) -dione or a salt thereof is subjected to a reduction reaction,
6- (4-aminophenyl) -1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) thieno [2,3-d] pyrimidine- obtained 2,4 (1H, 3H) -dione or a salt thereof is reacted with 1,1′-carbonyldiimidazole or a salt thereof and methoxyamine or a salt thereof,
1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2,3,4- A process for producing tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea or a salt thereof;
[8] Formula (I):

[Wherein, R ¹ represents a hydroxy group, a C _1-6 alkoxy group, or a C _1-6 alkoxy-pyridazinylamino group. ]
Or a salt thereof (in this specification, sometimes abbreviated as compound (I));
[9] Formula (II):

[Wherein R ² represents a nitro group or an amino group. ]
Or a salt thereof (in this specification, sometimes abbreviated as compound (II)).

According to the present invention, high-quality 1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2 in high yield , 4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea or a salt thereof can be produced more safely. In addition, high quality 1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2 , 3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea or a salt thereof can be easily and efficiently produced.
Compounds (I) and (II) are prepared from 1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4- It is useful as a raw material compound for producing dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea or a salt thereof.

FIG. 1 shows 1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2, 3 shows a powder X-ray diffraction pattern of tetrahydrofuran solvate crystals of 3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea. FIG. 2 shows 1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2, 3 shows a powder X-ray diffraction pattern of crystals of 3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea.

(Detailed description of the invention)
Definitions of terms used in the present invention will be described in detail below.

In the present specification, “C _1-6 alkoxy (group)” means, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy Etc. The C _1-6 alkoxy group represented by R ¹ is preferably ethoxy.
The “C _1-6 alkoxy-pyridazinylamino group” represented by R ¹ is a pyridazinylamino group substituted with 1 to 3 (preferably 1) C _1-6 alkoxy groups. Indicates. The “C _1-6 alkoxy-pyridazinylamino group” represented by R ¹ is preferably a 6-C _1-6 alkoxy-3-pyridazinylamino group. In particular, a 6-methoxy-3-pyridazinylamino group is preferable.

  In the present specification, “1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2, , 3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea ”is N- (4- (1- (2,6-difluoro) described in Patent Document 2. Benzyl) -5-((dimethylamino) methyl) -3- (6-methoxy-3-pyridazinyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine- 6-yl) phenyl) -N′-methoxyurea is the same compound.

Next, the manufacturing method of this invention is demonstrated.
Hereinafter, “room temperature” usually indicates 1 to 30 ° C.
In the following reaction, the raw material compound, the production intermediate and the target compound may be a salt. Examples of such salts, and salts in the compounds (I) and (II) include salts with inorganic acids, salts with organic acids, and salts with acidic amino acids. Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid. Preferable examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, and benzenesulfonic acid And salts with p-toluenesulfonic acid. Preferable examples of the salt with acidic amino acid include salts with aspartic acid and glutamic acid. Of these, pharmaceutically acceptable salts are preferred.
The compound obtained in each step can be used in the next reaction as a reaction mixture or as a crude product, but can also be isolated from the reaction mixture according to a conventional method, and can be separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be easily purified. When the compound in the formula is commercially available, a commercially available product can be used as it is.

(Process 1)

Ethyl 4-bromomethyl-2-[(2,6-difluorobenzyl) ethoxycarbonylamino] -5- (4-nitrophenyl) thiophene-3-carboxylate or a salt thereof (hereinafter also referred to as BNTC) is 2, In the presence of 2'-azobis (2,4-dimethylvaleronitrile) and trifluoromethylbenzene, ethyl 2-[(2,6-difluorobenzyl) ethoxycarbonylamino] -4-methyl-5- (4-nitro It can be produced by reacting phenyl) thiophene-3-carboxylate or a salt thereof (hereinafter also referred to as FNTC) with N-bromosuccinimide. This reaction can also be performed using a solvent.
The usage-amount of N-bromosuccinimide is 1.0-1.5 equivalent normally with respect to FNTC, Preferably, it is 1.1-1.4 equivalent, More preferably, it is 1.2-1.3 equivalent It is.
The amount of 2,2′-azobis (2,4-dimethylvaleronitrile) used is usually 0.01 to 0.2 equivalents, preferably 0.05 to 0.15 equivalents, relative to FNTC.
The usage-amount of trifluoromethylbenzene is 0.1-1.0 mL normally with respect to 1 mmol of FNTC, Preferably, it is 0.2-0.6 mL.
The solvent is not particularly limited as long as the reaction proceeds, and includes ethyl acetate, carbon tetrachloride, dichloromethane, dichloroethane, chlorobenzene, acetonitrile, and the like, and preferably ethyl acetate. Further, trifluoromethylbenzene or a mixed solution of trifluoromethylbenzene and an ester solvent such as ethyl acetate may be used as a solvent. The ratio (volume ratio) of the mixed solution is preferably 1: 0 to 1:50 in an ester solvent such as trifluoromethylbenzene: ethyl acetate, more preferably 1: 3 to 1:30.
The reaction temperature is usually 50-80 ° C, preferably 60-80 ° C, more preferably 65-75 ° C.
The reaction time is usually 0.1 to 5 hours, preferably 0.5 to 1 hour.
In this step, as a radical initiator, 2,2′-azobis (2,4-dimethylvaleronitrile), which is less toxic than 2,2′-azobisisobutyronitrile, is used. Compared with the reaction described in Patent Document 1, the bromination reaction can be performed more safely. Further, by using a less toxic ester solvent such as ethyl acetate and trifluoromethylbenzene as the solvent, the bromination reaction can be carried out more quickly than the reactions described in Patent Document 1 and Non-Patent Document 1. This can be performed and the generation of impurities can be suppressed.
In another embodiment, this reaction can also be performed in the absence of trifluoromethylbenzene. Even when performed in the absence of trifluoromethylbenzene, BNTC can be produced by the method described above or a method analogous thereto.
FNTC can be produced by the method described in Patent Document 1 or a method analogous thereto.

(Process 2)

Ethyl 2-[(2,6-difluorobenzyl) ethoxycarbonylamino] -4-dimethylaminomethyl-5- (4-nitrophenyl) thiophene-3-carboxylate or a salt thereof (hereinafter also referred to as ANTC) is It can be produced by reacting BNTC with dimethylamine or a salt thereof. This reaction can also be performed using a solvent. ANTC is compound (I) in which R ¹ is ethoxy.
The amount of dimethylamine or a salt thereof (preferably dimethylamine hydrochloride) used is usually 1.0 to 3.0 equivalents, preferably 1.2 to 1.8 equivalents, relative to BNTC.
In order to suitably proceed the reaction, a base may be used. Examples of the base include triethylamine and diisopropylethylamine. The usage-amount of a base is 1.0-5.0 equivalent normally with respect to BNTC, Preferably, it is 2.0-3.0 equivalent.
The solvent is not particularly limited as long as the reaction proceeds, and examples thereof include dimethylformamide (DMF), dimethylacetamide (DMAc), tetrahydrofuran, and the like, and preferably DMF. The usage-amount of a solvent is 0.5-10 mL normally with respect to 1 mmol of BNTC, Preferably, it is 2.0-4.0 mL.
The reaction temperature is generally 0-30 ° C, preferably 10-20 ° C.
The reaction time is usually 0.5 to 24 hours, preferably 1 to 2 hours.
Compound (I) wherein R ¹ is a C _1-6 alkoxy group can be produced by the method described in Step 2 or a method analogous thereto.

(Process 3)

2-[(2,6-difluorobenzyl) ethoxycarbonylamino] -4-dimethylaminomethyl-5- (4-nitrophenyl) thiophene-3-carboxylic acid or a salt thereof (hereinafter also referred to as NTCA) is ANTC. Can be produced by hydrolysis. This reaction can also be performed using a solvent. ANTC is compound (I) in which R ¹ is ethoxy.
Hydrolysis is performed using a base, and the base is not particularly limited, and a base known per se can be used. Examples of the base include potassium hydroxide, sodium hydroxide, and lithium hydroxide. Of these, potassium hydroxide is preferred. The usage-amount of a base is 1-2 equivalent normally with respect to ANTC, Preferably, it is 1.2-1.8 equivalent.
Hydrolysis is usually performed using a water-soluble organic solvent, and the water-soluble organic solvent is not particularly limited as long as the reaction proceeds, and examples thereof include ethanol, methanol, and tetrahydrofuran. The usage-amount of a solvent is 1-10 mL normally with respect to 1 mmol of ANTC, Preferably, it is 4-6 mL.
The reaction temperature is generally 0-80 ° C, preferably 55-65 ° C.
The reaction time is usually 1 to 24 hours, preferably 3 to 6 hours.
Compound (I) wherein R ¹ is a C _1-6 alkoxy group can be produced by the method described in Step 2 or a method analogous thereto.

(Process 4)

Ethyl (2,6-difluorobenzyl)-[4-dimethylaminomethyl-3- (6-methoxypyridazin-3-ylcarbamoyl) -5- (4-nitrophenyl) thiophen-2-yl] carbamate or a salt thereof ( (Hereinafter also referred to as NNTC) is NTCA and 3-amino-6-methoxypyridazine or a salt thereof (preferably 3-amino-6-methoxypyridazine hydrochloride) in the presence of propylphosphonic anhydride and a base. It can manufacture by making it react. This reaction can also be performed using a solvent.
NTCA is a compound (I) in which R ¹ is a hydroxy group. NNTC is compound (I) in which R ¹ is a 6-methoxy-3-pyridazinylamino group.
The usage-amount of 3-amino-6-methoxypyridazine or its salt is 1.0-3.0 equivalent normally with respect to NTCA, Preferably, it is 1.1-1.5 equivalent.
The amount of propylphosphonic anhydride used is usually 1.0 to 3.0 equivalents, preferably 1.1 to 1.5 equivalents, relative to NTCA.
Examples of the base include diisopropylethylamine and triethylamine. The usage-amount of a base is 1-4 equivalent normally with respect to NTCA, Preferably, it is 2-3 equivalent.
The solvent is not particularly limited as long as the reaction proceeds, and examples thereof include dimethylacetamide (DMAc), dimethylformamide, dimethylsulfoxide, tetrahydrofuran, acetonitrile, and ethyl acetate. The usage-amount of a solvent is 1-10 mL normally with respect to NTCA1mmol, Preferably, it is 2-4mL.
The reaction temperature is usually 0 to 80 ° C., preferably 50 to 60 ° C.
The reaction time is usually 1 to 24 hours, preferably 1 to 3 hours.
Compound (I) in which R ¹ is a C _1-6 alkoxy-pyridazinyl group can be produced by the method described in Step 4 or a method analogous thereto.
In addition, although 3-amino-6-methoxypyridazine or its salt (henceforth AMP) may use a commercial item, it can also be manufactured, for example with the following method.

(Step 4 ')

AMP can be produced by reacting 3-amino-6-chloropyridazine (hereinafter also referred to as ACP) with sodium methoxide. This reaction can also be performed using a solvent.
The amount of sodium methoxide used is usually 1.0 to 2.5 equivalents, preferably 1.1 to 1.5 equivalents, relative to ACP.
The solvent is not particularly limited as long as the reaction proceeds, and methanol, ethanol, toluene and the like can be mentioned. The usage-amount of a solvent is 0.1-10 mL normally with respect to ACP1mmol, Preferably, it is 0.5-1mL.
The reaction can also be carried out under high pressure. Usually, the internal pressure of the reaction vessel is 0.6 to 0.9 MPa, preferably 0.65 to 0.75 MPa.
The reaction temperature is usually 110 to 140 ° C, preferably 120 to 135 ° C.
The reaction time is usually 6 to 24 hours, preferably 7 to 9 hours.

(Process 5)

1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -6- (4-nitrophenyl) thieno [2,3-d] pyrimidine-2, 4 (1H, 3H) -dione or a salt thereof (hereinafter also referred to as NNTP) can be produced by subjecting NNTC to a cyclization reaction. This reaction is performed using a solvent. NNTC is compound (I) in which R ¹ is a 6-methoxy-3-pyridazinylamino group. NNTP is compound (II) in which R ² is a nitro group.
The cyclization reaction can be performed in the presence of a base, and the base is not particularly limited, and a base known per se can be used. Examples thereof include sodium methoxide and sodium ethoxide. . The usage-amount of a base is 0.01-2 equivalent normally with respect to NNTC, Preferably it is 0.02-0.1 equivalent.
As another aspect, the usage-amount of a base is 0.05-2 equivalent normally with respect to NNTC, Preferably, it is 0.1-1.0 equivalent.
The solvent is not particularly limited as long as the reaction proceeds, and examples thereof include methanol, ethanol, tetrahydrofuran, acetonitrile, or a mixed solvent thereof. The usage-amount of a solvent is 2-30 mL normally with respect to 1 mmol of NNTC, Preferably it is 3-5 mL.
As another aspect, the usage-amount of a solvent is 5-30 mL normally with respect to 1 mmol of NNTC, Preferably, it is 10-20 mL.
The reaction temperature is generally 0-80 ° C, preferably 20-65 ° C.
The reaction time is usually 0.5 to 24 hours, preferably 1 to 2 hours.

(Step 6)

6- (4-Aminophenyl) -1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) thieno [2,3-d] pyrimidine-2, 4 (1H, 3H) -dione or a salt thereof (hereinafter also referred to as NATP) can be produced by subjecting NNTP to a reduction reaction. NATP is a compound (II) in which R ² is an amino group. NNTP is a compound (II) in which R ² is a nitro group.
The reduction reaction can be performed in the presence of a catalyst. The catalyst is not particularly limited as long as it can be used for catalytic reduction, and examples thereof include palladium carbon, palladium hydroxide carbon, and platinum carbon. The usage-amount of a catalyst is 0.01-0.2g normally with respect to 1g of NNTP, Preferably, it is 0.05-0.2g.
An acid can also be added in order to suitably proceed the reaction. As the acid, hydrochloric acid, hydrogen chloride / methanol solution, formic acid, acetic acid and the like are preferable.
In the case of catalytic reduction, the hydrogen pressure is usually 0.05 to 0.4 MPa, preferably 0.1 to 0.3 MPa.
The reduction reaction can also be performed using a solvent. The solvent is not particularly limited as long as the reaction proceeds, and methanol, ethanol, tetrahydrofuran and the like can be mentioned. The usage-amount of a solvent is 1-10 mL normally with respect to NNTP1mmol, Preferably it is 4-6mL.
The reaction temperature is usually 10 to 40 ° C., preferably 20 to 30 ° C.
The reaction time is usually 1 to 24 hours, preferably 3 to 5 hours.

(Step 7)

1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2,3,4- Tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea or a salt thereof reacts with NATP, 1,1′-carbonyldiimidazole or a salt thereof, and methoxyamine or a salt thereof. Can be manufactured. NATP is a compound (II) in which R ² is an amino group.
The amount of 1,1′-carbonyldiimidazole or a salt thereof used is usually 1.0 to 3.0 equivalents relative to NATP, and the lower limit thereof is preferably 1.5 equivalents, more preferably 1.6 equivalents, and the upper limit is 3.0 equivalents, more preferably 2.5 equivalents. A suitable range is 1.6 to 2.5 equivalents, more preferably 1.6 to 1.8 equivalents.
The amount of methoxyamine or a salt thereof (preferably methoxyamine hydrochloride) is usually 1.0 to 3.0 equivalents relative to 1,1′-carbonyldiimidazole or a salt thereof, and the lower limit is preferably 1.05 equivalents, more preferably 1.1 equivalents, and the upper limit is 2.0 equivalents, more preferably 1.5 equivalents. A suitable range is 1.1 to 1.7 equivalents, more preferably 1.1 to 1.5 equivalents.
By using 1,1′-carbonyldiimidazole or a salt thereof, and methoxyamine or a salt thereof that are equal to or higher than the lower limit, the formation or residue of a related substance can be reduced, and a higher yield and purity of 1 -{4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2,3,4-tetrahydro Thieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea or a salt thereof can be obtained. In addition, the reaction can be carried out economically by using 1,1′-carbonyldiimidazole or a salt thereof and methoxyamine or a salt thereof which are not more than the above upper limit values.
In order to suitably proceed the reaction, a base can be added. The base is not particularly limited, and a base known per se can be used, and examples thereof include triethylamine and diisopropylethylamine. The amount of base used in the reaction is usually 0.5 to 3.0 equivalents, preferably 0.8 to 0.9 equivalents relative to NATP.
The reaction can also be performed using a solvent. The solvent is not particularly limited as long as the reaction proceeds, and examples thereof include acetonitrile, dimethylformamide, dimethyl sulfoxide, and dichloromethane.
The usage-amount of a solvent is 1-10 mL normally with respect to NATP1mmol, Preferably, it is 2-3mL.
The reaction temperature is generally 20-60 ° C, preferably 45-55 ° C.
The reaction time is usually 1 to 24 hours, preferably 1 to 2 hours.

(Process 8)
(1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2,3,4 -Purification of tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea or a salt thereof
(Step 8-1)
(1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2,3,4 -Preparation of tetrahydrofuran solvate crystals of tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea or a salt thereof)
1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2,3,4- Tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea or its salt is recrystallized with tetrahydrofuran to give 1- {4- [1- (2,6-difluorobenzyl). -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl } A tetrahydrofuran solvate crystal of 3-methoxyurea or a salt thereof can be produced.
The tetrahydrofuran solvate crystals can also be produced by adding tetrahydrofuran to the reaction mixture after completion of the reaction in the step 7.
The amount of tetrahydrofuran used is 1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo-1, It is 1-20 mL normally with respect to 1 g of 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea or its salt, Preferably it is 2-10 mL.
The solution or suspension used in the production of tetrahydrofuran solvate crystals (also referred to as crystallization) is usually stirred at 20 to 80 ° C, preferably 40 to 80 ° C, more preferably 30 to 50 ° C. Stir.
As another aspect, the solution in the production of tetrahydrofuran solvate crystals (also referred to as crystallization) is usually stirred at 40 to 80 ° C., preferably at 55 to 65 ° C.
The crystallization solution or suspension may contain water. In this case, the water content of the crude crystals is usually more than 0% and 50% or less, preferably 4 to 6%.
The crystallization time is usually 1 to 24 hours, preferably 1 to 2 hours.
The obtained crystals are dried by a method known per se to give 1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) To obtain tetrahydrofuran solvate crystals of -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea or a salt thereof. it can. Drying may be performed under reduced pressure or by ventilation. The drying temperature is preferably 70 ° C. or lower, and more preferably 40 to 60 ° C.

(Step 8-2)
(1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2,3,4 -Production of crystals of tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea or a salt thereof)
1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2,3,4- A tetrahydrofuran solvate crystal of tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea or a salt thereof is selected from the group consisting of dimethylsulfoxide, dimethylformamide and dimethylacetamide; By recrystallization using alkyl alcohol, 1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4 -Dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea or It is possible to produce a crystalline salt. By washing the obtained crystals with a solvent such as tetrahydrofuran, crystals of higher purity can be produced.
The amount of dimethyl sulfoxide, dimethylformamide or dimethylacetamide used is 1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2. , 4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea or a salt thereof, usually 1 g of tetrahydrofuran solvate crystals 1 to 5 mL, preferably 2 to 3 mL.
Examples of the alkyl alcohol include C _1-6 alkyl alcohol (eg, ethanol, methanol, isopropyl alcohol) and the like. Ethanol is preferable.
The amount of alkyl alcohol used is 1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo-1 , 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea or a salt thereof in a tetrahydrofuran solvate crystal of usually 13 to 18 mL, preferably 14-16 mL.
In another embodiment, the amount of alkyl alcohol used is 1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2, It is usually 15 per 1 g of tetrahydrofuran solvate crystals of 4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea or a salt thereof. -20 mL, preferably 16-18 mL.
Examples of the combination of one selected from the group consisting of dimethyl sulfoxide, dimethylformamide and dimethylacetamide with an alkyl alcohol include dimethyl sulfoxide and ethanol, dimethylformamide and ethanol, dimethylacetamide and ethanol, and the like. Preferred are dimethyl sulfoxide and ethanol.
The crystallization solution or suspension to be subjected to the recrystallization is usually stirred at 10 to 50 ° C., preferably 15 to 40 ° C.
In another embodiment, the crystallization solution is usually stirred at 20 to 50 ° C, preferably 30 to 40 ° C.
The crystallization time is usually 1 to 72 hours, preferably 24 to 72 hours.
In another embodiment, the crystallization time is usually 1 to 64 hours, preferably 12 to 24 hours.
The obtained crystals are dried by a method known per se to give 1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) A crystal of -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea or a salt thereof can be obtained. Drying may be performed by drying under reduced pressure or by ventilation. The drying temperature is preferably 70 ° C. or lower, and more preferably 40 to 60 ° C.
1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2,3,4- From tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea or a salt thereof, 1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl- 3- (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea or By producing a tetrahydrofuran solvate crystal of the salt and recrystallizing the tetrahydrofuran solvate crystal using the above-mentioned specific solvent, the contents of the related substances 1 to 3 described in the examples below are reduced. Higher purity 1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2, 3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea or a salt thereof can be produced.

1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2,3,4- The salt of tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea is not particularly limited as long as it is a pharmaceutically acceptable salt. For example, hydrochloric acid, hydrobromic acid, Salts with inorganic acids such as nitric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p- And salts with organic acids such as toluenesulfonic acid.
1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2,3,4- Tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea or salts thereof are diseases caused by gonadotropin releasing hormone (eg endometriosis, uterine fibroids and prostate cancer) It can be used for the prevention or treatment of the above-mentioned diseases by the method described in WO00 / 56739.

The present invention will be further described in detail with reference to the following reference examples, examples and test examples. These examples are merely implementations and do not limit the present invention, and do not depart from the scope of the present invention. It may be changed with. “Room temperature” in the following examples usually indicates about 10 ° C. to about 35 ° C. The ratio shown in the mixed solvent is a volume ratio unless otherwise specified. Unless otherwise indicated, “%” indicates “% by weight”.
In the following examples, nuclear magnetic resonance ( ¹ H-NMR) spectra were measured using a Varian Mercury-300 type nuclear magnetic resonance apparatus (300 MHz) with tetramethylsilane as an internal standard. In the description of the division mode, singlet, doublet, triplet, and multiplet are abbreviated as s, d, t, and m, respectively. The result of elemental analysis was ± 0.4% of the theoretical value. D8 ADVANCE (Bruker AXS) was used for powder X-rays. High performance liquid chromatography (HPLC) was measured under the following conditions described in each Reference Example and Examples.

Reference Example 1 (Production of 3-amino-6-methoxypyridazine hydrochloride)
Methanol (400 mL), 3-amino-6-chloropyridazine (64.0 g, 0.494 mol) and 28% sodium methoxide in methanol (114.5 g, 0.593 mol, 1.2 eq) were added to the high pressure reactor. It was. The reaction was performed at an internal temperature of 130 ° C. for 8 hours (internal pressure: about 0.7 MPa). The reaction solution was cooled, concentrated hydrochloric acid (12.8 mL) was added dropwise so as not to exceed 40 ° C., and the mixture was stirred for 20 minutes. Next, 25% aqueous ammonia (14.9 mL) was added dropwise so as not to exceed 40 ° C. The reaction solution was concentrated under reduced pressure to about 150 mL, and isopropyl alcohol (350 mL) was added. The solution was further concentrated under reduced pressure to about 150 mL, isopropyl alcohol (350 mL) was added, and the mixture was stirred for 30 minutes. Precipitated sodium chloride was filtered, and concentrated hydrochloric acid (38.2 mL) was added dropwise to the filtrate so as not to exceed 40 ° C. The mixture was concentrated to about 200 mL under reduced pressure, and isopropyl alcohol (300 mL) was added. Furthermore, it concentrated under reduced pressure to about 200 mL, isopropyl alcohol (300 mL) was added, and it stirred for 30 minutes. The crystallized crystals were collected by filtration, washed with isopropyl alcohol (50 mL), and dried under reduced pressure at 50 ° C. until constant weight, and crystals of 3-amino-6-methoxypyridazine hydrochloride (66.9 g, yield: 83). 8%, HPLC area percentage: 100%).

<HPLC conditions>
Detector: Ultraviolet absorptiometer (measurement wavelength 254 nm)
Column: YMC-Pack ODS-A A-302, 4.6 mm i. d. × 150
Mobile phase: 0.05M KH ₂ PO ₄ / CH ₃ CN = 8/2 (v / v)
Flow rate: 1.0 mL / min.
Measurement time: 30 minutes Analysis temperature: 25 ° C
Retention time: 3-amino-6-methoxypyridazine (1.9 min), 3-amino-6-chloropyridazine (2.6 min)

Reference Example 2 (Production of ethyl 2-amino-4-methyl-5- (4-nitrophenyl) thiophene-3-carboxylate)
Toluene (200 mL), 4-nitrophenylacetic acid (100.0 g, 0.552 mol) and N, N′-dimethylformamide (0.42 mL) were heated and stirred, and thionyl chloride (78.8 g) was heated at an internal temperature of 45 ± 5 ° C. 0.662 mol, 1.2 eq) was added dropwise. After stirring at an internal temperature of 45 ± 5 ° C. for 1 hour, the solution was concentrated under reduced pressure to about 238 mL to obtain an acid chloride solution. In a separate container, toluene (500 mL), magnesium diethoxide (75.8 g, 0.662 mol, 1.2 eq) and diethyl malonate (106.1 g, 0.662 mol, 1.2 eq) were added at an internal temperature of 65 ± 5. After stirring for 0.5 hours at 0 ° C., the internal temperature was cooled to 40 ° C. or lower. To this solution, the entire amount of the above acid chloride solution was added dropwise at an internal temperature of 35 ± 5 ° C., stirred at the same temperature for 0.5 hours, cooled to an internal temperature of 30 ° C. or lower, and 2N hydrochloric acid ( 413 g) was added dropwise. After standing, the organic layer was separated, washed with 10% brine (400 g), and concentrated under reduced pressure to about 250 mL. Acetic acid (176.0 g), water (112 mL) and concentrated sulfuric acid (39.0 g) were added to the residue, and the mixture was heated to reflux for 4 hours while distilling off volatiles. After cooling to an internal temperature of 15 ± 5 ° C. and adding ethyl acetate (450 mL), a 5N aqueous sodium hydroxide solution was added dropwise at an internal temperature of 10 to 30 ° C. to adjust the pH to 7.0. After standing, the organic layer was separated, washed with 10% brine (100 mL), and concentrated under reduced pressure to about 150 mL. Ethanol (240 mL), ethyl cyanoacetate (68.7 g, 0.607 mol, 1.1 eq), sulfur (19.5 g, 0.607 mol, 1.1 eq) were added to the residue, and the internal temperature was 20 to 45 ° C. -Butylamine (20.2 g, 0.276 mol, 0.5 eq) was added dropwise. After stirring at an internal temperature of 45 ± 5 ° C. for 2 hours, the mixture was cooled to an internal temperature of 25 ± 5 ° C. and stirred at the same temperature for 1 hour. The crystals were filtered, washed with ethanol (200 mL), dried under reduced pressure at 50 ° C. or lower, and red crystals of ethyl 2-amino-4-methyl-5- (4-nitrophenyl) thiophene-3-carboxylate (134. 9 g, yield: 79.8%, HPLC area percentage: 99.2%).

<HPLC conditions>
Detector: Ultraviolet absorptiometer (measurement wavelength 254 nm)
Column: YMC ODS-A A-302, 4.6 mm i. d. × 150mm
Mobile phase: 0.05M KH ₂ PO ₄ / CH ₃ CN = 3/7 (v / v)
Flow rate: 1.0 mL / min.
Measurement time: 45 minutes Analysis temperature: 25 ° C
Retention time: ethyl 2-amino-4-methyl-5- (4-nitrophenyl) thiophene-3-carboxylate (5.9 min)

Reference Example 3 (Production of ethyl 2-ethoxycarbonylamino-4-methyl-5- (4-nitrophenyl) thiophene-3-carboxylate)
Ethyl 2-amino-4-methyl-5- (4-nitrophenyl) thiophene-3-carboxylate (130.0 g, 0.424 mol) was suspended in toluene (390 mL) and heated under reflux with ethyl chloroformate (92 0.1 g, 0.849 mol, 2.0 eq) was added dropwise, and the mixture was stirred for 2 hours with heating under reflux. The internal temperature was cooled to 55 ± 5 ° C., ethanol (1170 mL) was added dropwise at the same temperature, the internal temperature was then cooled to 5 ± 5 ° C., and the mixture was stirred at the same temperature for 1 hour. The crystals were filtered, washed with ethanol (260 mL), and dried under reduced pressure at 45 ° C. to give yellow crystals of ethyl 2-ethoxycarbonylamino-4-methyl-5- (4-nitrophenyl) thiophene-3-carboxylate (154 0.2 g, yield: 96.1%, HPLC area percentage: 99.9%).

<HPLC conditions>
Detector: Ultraviolet absorptiometer (measurement wavelength 254 nm)
Column: YMC ODS-A A-302, 4.6 mm i. d. × 150mm
Mobile phase: 0.05M KH ₂ PO ₄ / CH ₃ CN = 3/7 (v / v)
Flow rate: 1.0 mL / min.
Measurement time: 45 minutes Analysis temperature: 25 ° C
Retention time: ethyl 2-amino-4-methyl-5- (4-nitrophenyl) thiophene-3-carboxylate (5.9 min), ethyl 2-ethoxycarbonylamino-4-methyl-5- (4-nitrophenyl) ) Thiophene-3-carboxylate (16.5 min)

Reference Example 4 (Production of ethyl 2-[(2,6-difluorobenzyl) ethoxycarbonylamino] -4-methyl-5- (4-nitrophenyl) thiophene-3-carboxylate)
Ethyl 2-ethoxycarbonylamino-4-methyl-5- (4-nitrophenyl) thiophene-3-carboxylate (150.0 g, 0.396 mol) was suspended in N, N′-dimethylacetamide (450 mL) and carbonated. Potassium (60.3 g, 0.436 mol, 1.1 eq), 35% 2,6-difluorobenzyl bromide / acetonitrile solution (257.9 g, 0.436 mol, 1.1 eq) was added. The mixture was heated and stirred at an internal temperature of 85 ± 5 ° C. for 2 hours, then cooled to an internal temperature of 55 ± 5 ° C., and ethyl acetate (1200 mL) and water (750 mL) were added. After standing, the organic layer was separated, washed with water (750 mL), and concentrated under reduced pressure to about 420 mL. Heptane (945 mL) was added to the residue, and the mixture was stirred at an internal temperature of 45 ± 5 ° C. for 1 hour and at an internal temperature of 5 ± 5 ° C. for 1 hour. The crystals were filtered, washed with ethyl acetate / heptane (1/3, 300 mL) at 5 ± 5 ° C., and dried under reduced pressure at 45 ± 5 ° C. to give ethyl 2-[(2,6-difluorobenzyl) ethoxycarbonylamino]. Pale yellow crystals (190.7 g, yield: 95.5%, HPLC area percentage: 99.9%) of -4-methyl-5- (4-nitrophenyl) thiophene-3-carboxylate were obtained.

<HPLC conditions>
Detector: Ultraviolet absorptiometer (measurement wavelength 254 nm)
Column: YMC ODS-A A-302, 4.6 mm i. d. × 150mm
Mobile phase: 0.05M KH ₂ PO ₄ / CH ₃ CN = 3/7 (v / v)
Flow rate: 1.0 mL / min.
Measurement time: 30 minutes Analysis temperature: 25 ° C
Retention time: ethyl 2-[(2,6-difluorobenzyl) ethoxycarbonylamino] -4-methyl-5- (4-nitrophenyl) thiophene-3-carboxylate (10.7 min), ethyl 2-ethoxycarbonylamino -4-Methyl-5- (4-nitrophenyl) thiophene-3-carboxylate (16.4 min)

Example 1 (Production of ethyl 4-bromomethyl-2-[(2,6-difluorobenzyl) ethoxycarbonylamino] -5- (4-nitrophenyl) thiophene-3-carboxylate)
Ethyl 2-[(2,6-difluorobenzyl) ethoxycarbonylamino] -4-methyl-5- (4-nitrophenyl) thiophene-3-carboxylate (1100.0 g, 2.180 mol) was added to ethyl acetate (8. 8L) and trifluoromethylbenzene (880 mL), and suspended in N-bromosuccinimide (NBS, 485.1 g, 2.725 mol, 1.25 eq), 2,2′-azobis (2,4-dimethylvaleronitrile). ) (V-65, 54.2 g, 0.218 mol, 0.1 eq) was added. The reaction solution was heated and stirred at 65 to 75 ° C. for 40 minutes. The reaction solution was cooled to 25 ± 5 ° C. and washed twice with city water (4.3 L). The ethyl acetate layer was concentrated to about 4 L under reduced pressure. Ethanol (3 L) was added, and the mixture was concentrated under reduced pressure to about 4 L. Again, ethanol (3 L) was added, and the mixture was concentrated under reduced pressure to about 4 L. Heptane (1.76 L) was added and stirred at 25 ± 5 ° C. for 30 minutes. Again, heptane (1.32 L) was added, and the mixture was stirred at 5 ± 5 ° C. for 1 hour. The crystals were filtered, washed with ethanol / heptane (1/2, 1.76 L), dried under reduced pressure at 45 ± 5 ° C., and ethyl 4-bromomethyl-2-[(2,6-difluorobenzyl) ethoxycarbonylamino]. A pale yellow crystal (1171 g, yield: 92.1%, HPLC area percentage: 92.9%) of -5- (4-nitrophenyl) thiophene-3-carboxylate was obtained.

<HPLC conditions>
Detector: Ultraviolet absorptiometer (measurement wavelength 254 nm)
Column: YMC ODS-A A-302, 4.6 mm i. d. × 150mm
Mobile phase: 0.05M KH ₂ PO ₄ / CH ₃ CN = 3/7 (v / v)
Flow rate: 1.0 mL / min.
Measurement time: 30 minutes Analysis temperature: 25 ° C
Retention time: ethyl 2-[(2,6-difluorobenzyl) ethoxycarbonylamino] -4-methyl-5- (4-nitrophenyl) thiophene-3-carboxylate (11.0 min), ethyl 4-bromomethyl- 2-[(2,6-difluorobenzyl) ethoxycarbonylamino] -5- (4-nitrophenyl) thiophene-3-carboxylate (12.3 min)

Example 2 (Production of ethyl 2-[(2,6-difluorobenzyl) ethoxycarbonylamino] -4-dimethylaminomethyl-5- (4-nitrophenyl) thiophene-3-carboxylate)
Dimethylamine hydrochloride (2.10 g, 25.71 mmol, 1.5 eq) was suspended in N, N′-dimethylformamide (DMF, 55 mL) and triethylamine (4.51 g, 44.57 mmol, 2.6 eq) was added. In addition, the mixture was stirred at 25 ± 5 ° C. for 30 minutes. Cool to 5 ± 5 ° C. and ethyl 4-bromomethyl-2-[(2,6-difluorobenzyl) ethoxycarbonylamino] -5- (4-nitrophenyl) thiophene-3-carboxylate (10 g, 17.14 mmol) And the vessel used for the compound was washed with DMF (5 mL). The reaction was stirred at 15 ± 5 ° C. for 1 hour. Ethanol (20 mL) was added at 20 ± 10 ° C., and the internal temperature was raised to 40 ± 5 ° C. City water (25 mL) was added at an internal temperature of 40 ± 5 ° C., stirred at the same temperature for 1 hour, and stirred at 25 ± 5 ° C. for 1 hour. The crystals were filtered, washed with ethanol / city water (4/1, 15 mL), dried under reduced pressure at 50 ± 5 ° C., and ethyl 2-[(2,6-difluorobenzyl) ethoxycarbonylamino] -4-dimethylamino. Yellow crystals of methyl-5- (4-nitrophenyl) thiophene-3-carboxylate (8.41 g, yield: 89.6%, HPLC area percentage: 99.6%) were obtained.

<HPLC conditions>
Detector: Ultraviolet absorptiometer (measurement wavelength 254 nm)
Column: YMC ODS-A A-302, 4.6 mm i. d. × 150mm
Mobile phase: 0.05M KH ₂ PO ₄ / CH ₃ CN = 3/7 (v / v)
Flow rate: 1.0 mL / min.
Measurement time: 30 minutes Analysis temperature: 25 ° C
Retention time: ethyl 2-[(2,6-difluorobenzyl) ethoxycarbonylamino] -4-dimethylaminomethyl-5- (4-nitrophenyl) thiophene-3-carboxylate (2.3 min), ethyl 4-bromomethyl -2-[(2,6-difluorobenzyl) ethoxycarbonylamino] -5- (4-nitrophenyl) thiophene-3-carboxylate (13.1 min)
¹ H-NMR (CDCl ₃ ) δ: 1.10-1.30 (3H, m), 1.31 (3H, t, J = 7.2 Hz), 2.07 (6H, s), 3.51 (2H, s), 4.10-4.30 (2H , m), 4.23 (2H, q, J = 7.2 Hz), 5.02 (2H, s), 6.85 (2H, t, J = 8.0 Hz), 7.66 (2H, d, J = 9.0 Hz), 8.24 (2H , d, J = 9.0 Hz).

Example 3 (Production of 2-[(2,6-difluorobenzyl) ethoxycarbonylamino] -4-dimethylaminomethyl-5- (4-nitrophenyl) thiophene-3-carboxylic acid)
Ethyl 2-[(2,6-difluorobenzyl) ethoxycarbonylamino] -4-dimethylaminomethyl-5- (4-nitrophenyl) thiophene-3-carboxylate (8.0 g, 14.61 mmol) in ethanol (72 mL) ) And city water (20.8 mL), 48% aqueous potassium hydroxide solution (2.56 g, 21.92 mmol, 1.5 eq) was added, and the mixture was stirred at 60 ± 5 ° C. for 5 hours. The reaction solution was cooled to 25 ± 5 ° C., and 6N hydrochloric acid was added to adjust the pH to 6.0 to 7.0. The adjustment solution was concentrated under reduced pressure to about 28 mL at 50 ° C. or lower. Ethanol (4 mL) and ethyl acetate (4 mL) were added at an internal temperature of 40 ± 5 ° C. City water (48 mL) was added at the same temperature, and the mixture was stirred at the same temperature for 1 hour. The internal temperature was cooled to 25 ± 5 ° C., and the mixture was stirred at the same temperature for 3 hours. The crystals were filtered, washed with ethanol / city water (1/9, 24 mL), and further washed with cooled ethyl acetate (24 mL). After drying under reduced pressure at 45 ± 5 ° C., yellow crystals of 2-[(2,6-difluorobenzyl) ethoxycarbonylamino] -4-dimethylaminomethyl-5- (4-nitrophenyl) thiophene-3-carboxylic acid (6 0.82 g, yield: 89.9%, HPLC area percentage: 98.7%).

<HPLC conditions>
Detector: Ultraviolet absorptiometer (measurement wavelength 254 nm)
Column: YMC ODS-A A-302, 4.6 mm i. d. × 150mm
Mobile phase: 0.05M KH ₂ PO ₄ / CH ₃ CN = 6/4 (v / v)
Flow rate: 1.0 mL / min.
Measurement time: 30 minutes Analysis temperature: 25 ° C
Retention time: 2-[(2,6-difluorobenzyl) ethoxycarbonylamino] -4-dimethylaminomethyl-5- (4-nitrophenyl) thiophene-3-carboxylic acid (8.4 min), ethyl 2-[( 2,6-difluorobenzyl) ethoxycarbonylamino] -4-dimethylaminomethyl-5- (4-nitrophenyl) thiophene-3-carboxylate (14.8 min)
¹ H-NMR (CDCl ₃ ) δ: 1.10-1.40 (3H, m), 2.37 (6H, s), 3.72 (2H, s), 4.10-4.35 (2H, m), 5.07 (2H, s), 6.84 (2H, t, J = 7.5 Hz), 7.15-7.30 (1H, m), 7.42 (2H, d, J = 8.8 Hz), 8.29 (2H, d, J = 8.8 Hz).

Example 4 (Ethyl (2,6-difluorobenzyl)-[4-dimethylaminomethyl-3- (6-methoxypyridazin-3-ylcarbamoyl) -5- (4-nitrophenyl) thiophen-2-yl] carbamate Manufacturing of)
Under a nitrogen atmosphere, 2-[(2,6-difluorobenzyl) ethoxycarbonylamino] -4-dimethylaminomethyl-5- (4-nitrophenyl) thiophene-3-carboxylic acid (6.5 g, 12.51 mmol) and 3-Amino-6-methoxypyridazine hydrochloride (2.43 g, 15.01 mmol, 1.2 eq) was added to N, N′-dimethylacetamide (DMAc, 29.25 mL) and ethyldiisopropylamine (25 ° C. at 25 ± 15 ° C.). 4.03 g, 31.28 mmol, 2.5 eq) was added. The internal temperature was raised to 55 ± 5 ° C. and stirred for 30 minutes. A 50.5% propylphosphonic anhydride (T3P) ethyl acetate solution (9.55 g, 15.01 mmol, 1.2 eq) was added dropwise at an internal temperature of 60 ° C. or lower, and the container used for the reagent was DMAc (3.25 mL). ). The mixture was stirred at an internal temperature of 55 ± 5 ° C. for 1 hour. The reaction solution was cooled to 25 ± 5 ° C., and city water (48.75 mL) was added dropwise at the same temperature. While vigorously stirring, 8N aqueous sodium hydroxide solution was added at 25 ± 5 ° C. to adjust the pH to 7.5 to 8.5, followed by stirring at 25 ± 5 ° C. for 30 minutes. The crystals were collected by filtration, washed with methanol (26 mL), dried under reduced pressure at 40 ± 5 ° C. until constant weight, and ethyl (2,6-difluorobenzyl)-[4-dimethylaminomethyl-3- (6-methoxy). Pyridazin-3-ylcarbamoyl) -5- (4-nitrophenyl) thiophen-2-yl] carbamate yellow crystals (7.61 g, yield: 97.0%, HPLC area percentage: 98.5%) were obtained. It was.

<HPLC conditions>
Detector: Ultraviolet absorptiometer (measurement wavelength 254 nm)
Column: YMC ODS-A A-302, 4.6 mm i. d. × 150mm
Mobile phase: 0.02M KH ₂ PO ₄ / CH ₃ CN = 4/6 (v / v)
Flow rate: 1.0 mL / min.
Measurement time: 40 minutes Analysis temperature: 25 ° C
Retention time: 3-amino-6-methoxypyridazine (1.7 min), 2-[(2,6-difluorobenzyl) ethoxycarbonylamino] -4-dimethylaminomethyl-5- (4-nitrophenyl) thiophene-3 -Carboxylic acid (2.5 min), ethyl (2,6-difluorobenzyl)-[4-dimethylaminomethyl-3- (6-methoxypyridazin-3-ylcarbamoyl) -5- (4-nitrophenyl) thiophene- 2-yl] carbamate (15.0 min)
¹ H-NMR (CDCl ₃ ) δ: 1.10-1.40 (3H, m), 2.20 (6H, s), 3.51 (2H, s), 4.10 (3H, m), 4.20-4.35 (2H, m), 5.03 (2H, s), 6.70-6.80 (2H, m), 6.99 (1H, d, J = 9.5 Hz), 7.10-7.20 (1H, m), 7.45-7.55 (2H, m), 8.25-8.35 (2H , m), 8.54 (1H, d, J = 9.5 Hz).

Example 5 (1- (2,6-Difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -6- (4-nitrophenyl) thieno [2,3-d] Preparation of pyrimidine-2,4 (1H, 3H) -dione hydrochloride)
Ethyl (2,6-difluorobenzyl)-[4-dimethylaminomethyl-3- (6-methoxypyridazin-3-ylcarbamoyl) -5- (4-nitrophenyl) thiophen-2-yl] carbamate (7.5 g 11.97 mmol), methanol (187.5 mL, 25 v / w), tetrahydrofuran (12.75 mL, 1.7 v / w) and 28% sodium methoxide in methanol (0.46 g, 2.39 mmol, 0.2 eq) ) Was stirred at 60 ± 5 ° C. for 1 hour. After cooling to 25 ± 5 ° C., concentrated hydrochloric acid (2.87 g, 28.73 mmol, 2.4 eq) was added dropwise and stirred for 20 minutes. Further, isopropyl alcohol (75 mL) was added, and the mixture was stirred at 25 ± 5 ° C. for 20 minutes and stirred at 5 ± 5 ° C. for 40 minutes. The crystals were collected by filtration, washed with cooled methanol / isopropyl alcohol (1/1, 22.5 mL), dried under reduced pressure at an internal temperature of 60 ° C. or lower (external temperature 55 ± 5 ° C.), and 1- (2,6- Difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -6- (4-nitrophenyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H)- Yellow crystals of dione hydrochloride (7.24 g, yield: 98.0%, HPLC area percentage: 99.9%) were obtained.

<HPLC conditions>
Detector: Ultraviolet absorptiometer (measurement wavelength 254 nm)
Column: YMC ODS-A A-302, 4.6 mm i. d. × 150mm
Mobile phase: 0.02M KH ₂ PO ₄ / CH ₃ CN = 4/6 (v / v)
Flow rate: 1.0 mL / min.
Measurement time: 40 minutes Analysis temperature: 25 ° C
Retention time: ethyl (2,6-difluorobenzyl)-[4-dimethylaminomethyl-3- (6-methoxypyridazin-3-ylcarbamoyl) -5- (4-nitrophenyl) thiophen-2-yl] carbamate ( 15.0 min), 1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -6- (4-nitrophenyl) thieno [2,3-d Pyrimidine-2,4 (1H, 3H) -dione (2.5 min)
¹ H-NMR (CDCl ₃ ) δ: 2.20 (6H, s), 3.72 (2H, s), 4.19 (3H, s), 5.38 (2H, brs), 6.95 (2H, t, J = 8.2 Hz), 7.14 (1H, d, J = 9.0 Hz), 7.20-7.35 (1H, m), 7.42 (1H, d, J = 9.0 Hz), 7.89 (2H, d, J = 8.8 Hz), 8.28 (2H, d , J = 8.8 Hz).

Example 6 (6- (4-Aminophenyl) -1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) thieno [2,3-d] Pyrimidine-2,4 (1H, 3H) -dione (production of RS-2 (related substance 2) in this specification))
1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -6- (4-nitrophenyl) thieno [2,3-d] pyrimidine-2, Methanol (640 mL) and concentrated hydrochloric acid (10.8 g, 103.68 mmol, 0.8 eq) were added to 4 (1H, 3H) -dione hydrochloride (80.0 g, 129.66 mmol). 10% Pd—C NX type (8.0 g, 50% water-containing product) was added in a nitrogen atmosphere, and the mixture was stirred and reacted at a hydrogen pressure of 0.2 ± 0.1 MPa and 25 ± 5 ° C. for 4 hours. Triethylamine was added to the reaction solution at 25 ± 5 ° C. to adjust the pH to 6.5 ± 0.5. Activated carbon (Shirakaba A, 4.0 g) was added and stirred for 20 to 60 minutes. Activated carbon and the catalyst were removed by filtration and washed with methanol (160 mL). The filtrate was warmed to 40 ± 5 ° C., and triethylamine was added to adjust the pH to 8.0 to 8.5. The mixture was aged with stirring at 40 ± 5 ° C. for about 30 minutes, cooled to 5 ± 5 ° C., and aged with stirring for about 2 hours. The crystals were collected by filtration, washed with methanol (160 mL), and dried under reduced pressure at 45 ± 5 ° C. until a constant weight was obtained. Almost white 6- (4-aminophenyl) -1- (2,6-difluorobenzyl)- Crystals of 5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (60.06 g, yield: 84. 1%, HPLC area percentage: 99%).

<HPLC conditions>
Detector: Ultraviolet absorptiometer (measurement wavelength 254 nm)
Column: YMC ODS-A A-302, 4.6 mm i. d. × 150mm
Mobile phase: 0.05M KH ₂ PO ₄ (pH 7.0 by 10% KOH) / CH ₃ CN = 55/45 (v / v)
Flow rate: 1.0 mL / min.
Measurement time: 30 minutes Analysis temperature: 25 ° C
Retention time: 6- (4-aminophenyl) -1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) thieno [2,3-d] pyrimidine -2,4 (1H, 3H) -dione (4.0 min), 1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -6- ( 4-Nitrophenyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (16 min)
¹ H-NMR (CDCl ₃ ) δ: 2.09 (6H, s), 3.40-3.70 (2H, br), 3.78 (2H, s), 4.14 (3H, s), 5.31 (2H, brs), 6.66 (2H , d, J = 8.6 Hz), 6.88 (2H, t, J = 7.6 Hz), 7.07 (1H, d, J = 9.2 Hz), 7.15-7.25 (1H, m), 7.27 (2H, d, J = 8.0 Hz), 7.38 (1H, d, J = 9.2 Hz).

Example 7 (1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2, Preparation of tetrahydrofuran solvate crystals of 3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea)
A reaction vessel was charged with acetonitrile (30 mL) and 1,1′-carbonyldiimidazole (CDI, 5.01 g, 30.90 mmol, 1.7 eq) and stirred. Triethylamine (1.56 g, 15.42 mmol, 0.85 eq) was added under stirring and cooled to an internal temperature of 10 ± 5 ° C. Methoxyamine hydrochloride (2.90 g, 34.72 mmol, 1.91 eq) was added in portions under stirring at an internal temperature of 30 ° C. or lower, and the container used for the reagent was washed with acetonitrile (5 mL). The mixture was stirred at an internal temperature of 25 ± 5 ° C. After confirming that the mixture had dissolved, the solution was stirred for 10 minutes or more. 6- (4-Aminophenyl) -1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) thieno [2,3-d] pyrimidine-2, 4 (1H, 3H) -dione (10.00 g, 18.16 mmol) was added under stirring and the vessel used for the reagent was washed with acetonitrile (5 mL). The reaction solution was heated to an internal temperature of 50 ± 5 ° C. and stirred at the same temperature for 2 hours to obtain a reaction solution (hereinafter abbreviated as reaction mixture A). Triethylamine (2.35 g, 23.22 mmol, 1.28 eq) was added with stirring at an internal temperature of 50 ± 5 ° C. City water (40 mL) was added dropwise at an internal temperature of 40 to 55 ° C., stirred for 1 hour, and city water (100 mL) was added dropwise at an internal temperature of 40 to 55 ° C. The mixture was aged with stirring at an internal temperature of 25 ± 5 ° C. for 1 hour or longer. The crystals were collected by filtration and washed with a mixed solution of city water (16 mL) and acetonitrile (4 mL) to obtain wet crystals. Tetrahydrofuran (50 mL) was charged into wet crystals, heated to an internal temperature of 60 ± 5 ° C., and suspended and stirred at the same temperature for about 1 hour. The internal temperature was cooled to 5 ± 5 ° C., and the mixture was stirred and aged at the same temperature for about 2 hours. The crystals were collected by filtration, washed with tetrahydrofuran (10 mL), and dried under reduced pressure at an external temperature of 50 ± 10 ° C. to give 1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- Tetrahydrofuran solvent of (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea A hydrate crystal (11.49 g, yield 90.9%) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 1.80-1.90 (4H, m), 2.13 (6H, s), 3.60-3.80 (6H, m), 3.82 (3H, s), 4.18 (3H, s), 5.35 (2H, brs), 6.92 (2H, t, J = 8.2 Hz), 7.12 (1H, d, J = 8.8 Hz), 7.20-7.60 (7H, m), 7.65 (1H, s).
Anal Calcd for C ₃₃ H ₃₅ F ₂ N ₇ O ₆ S: C, 56.97; H, 5.07; N, 14.09.
Found: C, 56.81; H, 5.17; N, 13.92.

  1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2,3,4 A powder X-ray diffraction pattern of tetrahydrofuran solvate crystals of -tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea is shown in FIG.

<Measurement conditions of powder X-ray diffraction>
Tube voltage: 40 kV
Tube current: 40 mA
Counting time: 0.2 sec / step
Step width: 0.02 ° Scanning range: 2θ = 3-40 °

  In addition, Table 1 shows characteristic peaks in the powder X-ray diffraction pattern.

Example 8 (1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2, Preparation of 3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea crystals)
In a reaction vessel, dimethyl sulfoxide (DMSO, 20 mL), 1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4 -Dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea tetrahydrofuran solvate crystals (8.93 g) were charged, and the internal temperature was 35. Heated to ± 5 ° C. and dissolved. After confirmation of dissolution, ethanol (20 mL) was added at an internal temperature of 35 ± 5 ° C. The mixture was filtered through a dust filter and washed with ethanol (8 mL). Ethanol (112 mL) was added at an internal temperature of 35 ± 5 ° C., stirred at an internal temperature of 35 ± 5 ° C. for 1 hour or longer, cooled to an internal temperature of 25 ± 5 ° C., and stirred at the same temperature for 12 hours or longer. The crystals were collected by filtration, washed with ethanol (16 mL), and dried under reduced pressure at an external temperature of 50 ± 10 ° C. to give 1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-Methoxypyridazin-3-yl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea (7. 33 g, yield 91.6%) was obtained as white crystals.

  The powder X-ray diffraction pattern of the white crystal is shown in FIG.

<Measurement conditions of powder X-ray diffraction>
Tube voltage: 40 kV
Tube current: 40 mA
Counting time: 0.2 sec / step
Step width: 0.02 ° Scanning range: 2θ = 3-40 °

  In addition, Table 2 shows characteristic peaks in the powder X-ray diffraction pattern.

Example 9
According to the method of Example 7, an experiment was conducted in which the equivalent (eq) of 1,1′-carbonyldiimidazole (CDI) and methoxyamine hydrochloride was changed. Table 4 shows 1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) in the reaction mixture A obtained in the above experiment. 2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea (referred to in the table as “Compound A”) and RS -2 content. In the table, the equivalent of CDI represents the equivalent to NATP, and the equivalent of methoxyamine hydrochloride represents the equivalent to CDI.

The HPLC measurement conditions in Example 9 and Test Example 1 are as shown below.
<HPLC conditions>
Detector: UV absorptiometer (measurement wavelength 230 nm)
Column: Sunfire C18 S-3.5 μm, 4.6 mm i. d. × 10cm
(Waters)
Mobile phase: (A) 0.05 mol / L phosphate buffer (pH 2.0) / acetonitrile mixture (31: 9 (volume ratio))
(B) 0.05 mol / L phosphate buffer solution (pH 2.0) / acetonitrile mixture (12:13 (volume ratio))

Gradient program (linear)

Flow rate: 1.0 mL / min.
Measurement time: 60 minutes Analysis temperature: 40 ° C
Retention time: 6- (4-aminophenyl) -1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) thieno [2,3-d] pyrimidine -2,4 (1H, 3H) -dione (7.3 min), 1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazine-3- Yl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea (15.5 min)

  Table 4 shows that in the production shown in Example 7, 1.6 to 2.5 equivalents of CDI with respect to NATP and 1.1 to 1.5 equivalents of methoxyamine hydrochloride with respect to CDI were used. , High-quality 1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2, low content of RS-2, It has been found that 4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea can be obtained.

Test example 1
In each of the crystals obtained in Examples 7 and 8, 1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2, 4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea (referred to as “Compound A” in the table) and related substances (specific Specifically, the results of measuring the contents of RS-1, RS-2 and RS-3) are shown in Table 5.

  From Table 5, 1- {4- [1- (2,6-difluorobenzyl) -5 in the tetrahydrofuran solvate crystal in Example 7 and the white crystal in Example 8 as compared with the wet crystal in Example 7. -Dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl}- A high 3-methoxyurea content is indicated. Therefore, according to the methods of Example 7 and Example 8, high-quality 1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- with a low content of related substances is obtained. (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea can be obtained. It has been found.

Example 10 (1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-2,4-dioxo-3- (6-oxo-1,6-dihydropyridazin-3-yl) ) -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea (also referred to as RS-1 (related substance 1) in this specification) Manufacturing of)
1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2,3,4- Tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea (0.50 g, 0.80 mmol) was dissolved in DMSO (1.5 mL) and concentrated hydrochloric acid (0.32 g, 3 .2 mmol) was added. The reaction was stirred at 80 ° C. for 2 hours. Sodium bicarbonate water (0.27 g, 3.2 mmol) and water (3 mL) were added at room temperature, the precipitate was collected by filtration, washed with water (30 mL), dried at 50 ° C. under reduced pressure, and 1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-2,4-dioxo-3- (6-oxo-1,6-dihydropyridazin-3-yl) -1,2,3,4 -Crystals of tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea (0.19 g, 39%) were obtained.
¹ H-NMR (CDCl ₃ ) δ: 2.06 (6H, s), ca.3.54 (1H, m), ca.3.63 (1H, m), 3.65 (3H, s), ca.5.18 (1H, m) , ca.5.40 (1H, m), 7.07 (1H, d, J = 9.8 Hz), ca.7.14 (1H, m), ca.7.47 (1H, m), ca.7.51 (1H, m), ca .7.52 (2H, m), ca.7.72 (2H, m), 9.08 (1H, s), 9.63 (1H, s), 13.29 (1H, s).
IR (KBr): 1719, 1676, 1591, 1528, 1470, 1410, 1331, 1034 cm ^-1 .
ESI-MS m / z: 610.17 [M + H] ⁺ , 608.15 [MH] ^- .
Anal Calcd for C ₂₇ H ₂₄ F ₂ N ₆ O ₃ S ・ 0.1H ₂ O: C, 58.71; H, 4.42; N, 15.21.
Found: C, 58.43; H, 4.39; N, 15.19.

Example 11 (N- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2, 3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -N, N′-dimethoxydicarbonimidic acid diamide (also referred to herein as RS-3 (related substance 3)) Manufacturing of)
Crude 1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2,3 , 4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea was fractionated by HPLC, and the structure was determined from the following spectral data.
¹ H-NMR (CDCl ₃ ) δ: 2.05 (6H, s), ca.3.54 (1H, m), ca.3.67 (1H, m), 3.70 (3H, s), 3.80 (3H, s), 4.10 (3H, s), ca.5.22 (1H, m), ca.5.39 (1H, m), ca.7.14 (2H, m), ca.7.46 (1H, m), ca.7.47 (1H, m) , ca.7.62 (2H, m), ca.7.64 (2H, m), ca.7.76 (1H, m), 10.30 (1H, s), 11.34 (1H, s).
IR (KBr): 1714, 1674, 1591, 1528, 1460, 1410, 1306, 1036 cm ^-1 .
ESI-MS m / z: 697.20 [M + H] ⁺ , 719.18 [M + Na] ⁺ .
Anal Calcd for C ₃₁ H ₃₀ F ₂ N ₈ O ₇ S ・ 1.0H ₂ O: C, 52.10; H, 4.51; N, 15.68.
Found: C, 52.17; H, 4.52; N, 15.78.

Example 12 Preparation of ethyl 4-bromomethyl-2-[(2,6-difluorobenzyl) ethoxycarbonylamino] -5- (4-nitrophenyl) thiophene-3-carboxylate
Ethyl 2-[(2,6-difluorobenzyl) ethoxycarbonylamino] -4-methyl-5- (4-nitrophenyl) thiophene-3-carboxylate (50 g, 99.11 mmol) was combined with ethyl acetate (300 mL) and tris. The suspension was suspended in a mixed solution of fluoromethylbenzene (40 mL) and purged with nitrogen. N-bromosuccinimide (NBS, 22.05 g, 123.89 mmol, 1.25 eq) and 2,2′-azobis (2,4-dimethylvaleronitrile) (V-65, 1.97 g at an internal temperature of 70 ± 5 ° C. , 7.93 mmol, 0.08 eq) in ethyl acetate (90 mL) was added and the vessel used for the suspension was washed with ethyl acetate (10 mL).
The reaction solution was heated and stirred at 65 to 75 ° C. for 40 minutes. The reaction solution was cooled to 25 ± 5 ° C. and washed twice with city water (195 mL). The ethyl acetate layer was concentrated under reduced pressure to about 165 mL. Ethanol (135 mL) was added, and the mixture was concentrated under reduced pressure to about 155 mL. Ethanol (135 mL) was added again, heptane (130 mL) was further added, and the mixture was stirred at 25 ± 5 ° C. for 30 minutes. Again, heptane (100 mL) was added, and the mixture was stirred at 5 ± 5 ° C. for 1 hour. The crystals were collected by filtration, washed with ethanol / heptane (1/2, 80 mL), and then dried under reduced pressure at 45 ± 5 ° C. to give ethyl 4-bromomethyl-2-[(2,6-difluorobenzyl) ethoxycarbonylamino]- A slightly yellow crystal (50.4 g, yield: 92.1%, HPLC area percentage: 94.3%) of 5- (4-nitrophenyl) thiophene-3-carboxylate was obtained.

<HPLC conditions>
Detector: Ultraviolet absorptiometer (measurement wavelength 254 nm)
Column: YMC ODS-A A-302, 4.6 mm i. d. × 150mm
Mobile phase: 0.05M KH ₂ PO ₄ / CH ₃ CN = 3/7 (v / v)
Flow rate: 1.0 mL / min.
Measurement time: 40 minutes Analysis temperature: 25 ° C
Retention time: ethyl 2-[(2,6-difluorobenzyl) ethoxycarbonylamino] -4-methyl-5- (4-nitrophenyl) thiophene-3-carboxylate (11.5 min), ethyl 4-bromomethyl-2 -[(2,6-difluorobenzyl) ethoxycarbonylamino] -5- (4-nitrophenyl) thiophene-3-carboxylate (13 min)

Example 13 (1- (2,6-Difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -6- (4-nitrophenyl) thieno [2,3-d] Preparation of pyrimidine-2,4 (1H, 3H) -dione hydrochloride)
Ethyl (2,6-difluorobenzyl)-[4-dimethylaminomethyl-3- (6-methoxypyridazin-3-ylcarbamoyl) -5- (4-nitrophenyl) thiophen-2-yl] carbamate (30.0 g , 47.88 mmol) was suspended in acetonitrile (210 mL), and 28% sodium methoxide in methanol (0.46 g, 2.39 mmol, 0.05 eq) was added at an internal temperature of 25 ± 5 ° C. and used as the reagent. The vessel was washed with methanol (0.3 mL). After stirring at an internal temperature of 25 ± 5 ° C. for 1 hour, the crystals were collected by filtration, washed with acetonitrile (60 mL), and 1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazine). -3-yl) -6- (4-nitrophenyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione was obtained.
A reaction vessel was charged with methanol (90 mL), isopropyl alcohol (150 mL), concentrated hydrochloric acid (5.49 g, 52.66 mmol, 1.1 eq), and 1- (2,6-difluorobenzyl)-at an internal temperature of 25 ± 5 ° C. Add 5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -6- (4-nitrophenyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione The container used for the compound was washed with isopropyl alcohol (30 mL). After stirring at an internal temperature of 25 ± 5 ° C. for 0.5 hour, the mixture was cooled to an internal temperature of 5 ± 5 ° C. and stirred at the same temperature for 1 hour. The crystals were collected by filtration, washed with methanol / isopropyl alcohol (1/2, 60 mL, cooled to 5 ± 5 ° C.), dried under reduced pressure at 50 ± 5 ° C., and 1- (2,6-difluorobenzyl)- Of 5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -6- (4-nitrophenyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione hydrochloride Yellow crystals (29.3 g, yield: 99.2%, HPLC area percentage: 99.8%) were obtained.

<HPLC conditions>
Detector: Ultraviolet absorptiometer (measurement wavelength 254 nm)
Column: YMC ODS-A A-302, 4.6 mm i. d. × 150mm
Mobile phase: 0.02M KH ₂ PO ₄ / CH ₃ CN = 4/6 (v / v)
Flow rate: 1.0 mL / min.
Measurement time: 40 minutes Analysis temperature: 25 ° C
Retention time: ethyl (2,6-difluorobenzyl)-[4-dimethylaminomethyl-3- (6-methoxypyridazin-3-ylcarbamoyl) -5- (4-nitrophenyl) thiophen-2-yl] carbamate ( 10.5 min), 1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -6- (4-nitrophenyl) thieno [2,3-d Pyrimidine-2,4 (1H, 3H) -dione (2.9 min)

Example 14 (6- (4-Aminophenyl) -1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) thieno [2,3-d] Pyrimidine-2,4 (1H, 3H) -dione (production of RS-2 (related substance 2) in this specification))
1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -6- (4-nitrophenyl) thieno [2,3-d] pyrimidine-2, To 4 (1H, 3H) -dione hydrochloride (9.0 g, 14.59 mmol) was added methanol (72 mL) and concentrated hydrochloric acid (1.22 g, 11.67 mmol, 0.8 eq). 10% Pd—C NX type (0.9 g, 50% water-containing product) was added in a nitrogen atmosphere, and the mixture was stirred at a hydrogen pressure of 0.2 ± 0.1 MPa and 25 ± 5 ° C. for 4 hours. Triethylamine was added to the reaction solution at 25 ± 5 ° C. to adjust the pH to 6.5 ± 0.5. Activated carbon (Shirakaba A, 0.45 g) was added and stirred for 20 to 60 minutes. Activated charcoal and catalyst were removed by filtration and washed with methanol (18 mL). The filtrate was warmed to 40 ± 5 ° C., and triethylamine was added to adjust the pH to 8.0 to 8.5. After stirring and aging at 40 ± 5 ° C. for about 30 minutes, the mixture was cooled to 5 ± 5 ° C. and stirred and aged for 1 hour. The crystals were collected by filtration, washed twice with methanol (18 mL), dried under reduced pressure at 45 ± 5 ° C. until a constant weight was obtained, and almost white 6- (4-aminophenyl) -1- (2,6-difluorobenzyl was obtained. ) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione crystals (6.93 g, yield: 86.3%, HPLC area percentage: 99.5%).

<HPLC conditions>
Detector: Ultraviolet absorptiometer (measurement wavelength 254 nm)
Column: YMC ODS-A A-302, 4.6 mm i. d. × 150mm
Mobile phase: 0.05M KH ₂ PO ₄ (pH 7.0 by 10% KOH) / CH ₃ CN = 55/45 (v / v)
Flow rate: 1.0 mL / min.
Measurement time: 30 minutes Analysis temperature: 25 ° C
Retention time: 6- (4-aminophenyl) -1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) thieno [2,3-d] pyrimidine -2,4 (1H, 3H) -dione (4.8 min), 1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -6- ( 4-Nitrophenyl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (16 min)

Example 15 (1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2, Preparation of tetrahydrofuran solvate crystals of 3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea)
A reaction vessel was charged with acetonitrile (60 mL) and 1,1′-carbonyldiimidazole (CDI, 10.1 g, 61.75 mmol, 1.7 eq) and stirred. Triethylamine (3.12 g, 30.88 mmol, 0.85 eq) was added under stirring and cooled to an internal temperature of 10 ± 5 ° C. Methoxyamine hydrochloride (5.79 g, 69.38 mmol, 1.91 eq) was added in portions under stirring at an internal temperature of 30 ° C. or lower, and the container used for the reagent was washed with acetonitrile (10 mL). The mixture was stirred at an internal temperature of 25 ± 5 ° C. After confirming that the mixture had dissolved, the solution was stirred for 10 minutes or more. 6- (4-Aminophenyl) -1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) thieno [2,3-d] pyrimidine-2, 4 (1H, 3H) -dione (20.00 g, 36.33 mmol) was added under stirring and the vessel used for the reagent was washed with acetonitrile (10 mL). The reaction solution was heated to an internal temperature of 50 ± 5 ° C. and stirred at the same temperature for 1 hour to obtain a reaction solution. Further, triethylamine (4.70 g, 46.50 mmol, 1.28 eq) was added with stirring at an internal temperature of 50 ± 5 ° C. City water (80 mL) was added dropwise at an internal temperature of 40 to 55 ° C., and after stirring for 1 hour, city water (200 mL) was added dropwise at an internal temperature of 40 to 55 ° C. The mixture was aged with stirring at an internal temperature of 25 ± 5 ° C. for 1 hour or longer. The crystals were collected by filtration, washed with a mixture of city water (32 mL) and acetonitrile (8 mL), and dried under reduced pressure at 50 ± 10 ° C. to obtain crude crystals (21.92 g). Crude crystals (21.0 g) were suspended in tetrahydrofuran (100 mL), and water was added to the crude crystals so that the water content was 5%. Then, the internal temperature was raised to 40 ± 5 ° C. The suspension was stirred for an hour. The internal temperature was cooled to 5 ± 5 ° C., and the mixture was stirred at the same temperature for 1 hour. The crystals were collected by filtration, washed with tetrahydrofuran (40 mL), and dried under reduced pressure at an external temperature of 50 ± 10 ° C. to give 1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- Tetrahydrofuran solvent of (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea A hydrate crystal (22.56 g, yield 93.2%, HPLC area percentage: 99.8%) was obtained.

Example 16 (1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2, Preparation of 3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea crystals)
Dimethyl sulfoxide (20 mL) and 1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo were added to the reaction vessel. -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea in tetrahydrofuran solvate crystals (11.16 g) was charged, and the internal temperature was 35 ± 5. Warmed to 0 ° C. to dissolve. After confirmation of dissolution, the solution was filtered with a dust filter and washed with dimethyl sulfoxide (5 mL). Ethanol (55 mL) was added at an internal temperature of 35 ± 5 ° C., the seed crystals (10 mg) obtained in Reference Example 5 were added, and the mixture was stirred at an internal temperature of 35 ± 5 ° C. for 17 hours. Ethanol (120 mL) was added dropwise at an internal temperature of 35 ± 5 ° C., and then cooled to an internal temperature of 15 ± 5 ° C. and stirred at the same temperature for about 31 hours. The crystals were collected by filtration, washed with ethanol (20 mL, cooled to 15 ± 5 ° C.) and then dried under reduced pressure at an external temperature of 50 ± 10 ° C. to give 1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl } -3-methoxyurea (9.04 g, yield 90.4%, HPLC area percentage: 99.8%) was obtained as white crystals.

The HPLC measurement conditions in Example 15 and Example 16 are as shown below.
<HPLC conditions>
Detector: UV absorptiometer (measurement wavelength 230 nm)
Column: Sunfire C18 S-3.5 μm, 4.6 mm i. d. × 10cm (Waters)
Mobile phase: (A) 0.05 mol / L phosphate buffer (pH 2.0) / acetonitrile mixture (31: 9 (volume ratio))
(B) 0.05 mol / L phosphate buffer solution (pH 2.0) / acetonitrile mixture (12:13 (volume ratio))

Gradient program (linear)

Flow rate: 1.0 mL / min.
Measurement time: 60 minutes Analysis temperature: 40 ° C
Retention time: 6- (4-aminophenyl) -1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) thieno [2,3-d] pyrimidine -2,4 (1H, 3H) -dione (7.7 min), 1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazine-3- Yl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea (14.5 min)

Reference Example 5 (1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2, Production of seed crystals of 3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea)
To the reaction vessel was added dimethyl sulfoxide (25 mL) and 1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo. -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea (10.00 g) was charged and heated to an internal temperature of 35 ± 5 ° C. Dissolved. After confirmation of dissolution, ethanol (35 mL) was added at an internal temperature of 35 ± 5 ° C., and the mixture was stirred at an internal temperature of 35 ± 5 ° C. for 5 days. After confirming that the powder X-ray diffraction pattern of the precipitated crystals shows the same pattern as in FIG. 2, ethanol (140 mL) was added dropwise at an internal temperature of 35 ± 5 ° C., and the internal temperature was cooled to 25 ± 5 ° C. For about 3 days. The crystals were collected by filtration, washed with ethanol (20 mL, cooled to 25 ± 5 ° C.) and dried under reduced pressure at an external temperature of 50 ± 10 ° C. to give 1- {4- [1- (2,6-difluorobenzyl). -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl } -3-Methoxyurea seed crystals (8.24 g, yield 82.4%) were obtained as white crystals.

<HPLC conditions>
Detector: UV absorptiometer (measurement wavelength 230 nm)
Column: Sunfire C18 S-3.5 μm, 4.6 mm i. d. × 10cm (Waters)
Mobile phase: (A) 0.05 mol / L phosphate buffer (pH 2.0) / acetonitrile mixture (31: 9 (volume ratio))
(B) 0.05 mol / L phosphate buffer solution (pH 2.0) / acetonitrile mixture (12:13 (volume ratio))

Gradient program (linear)

Flow rate: 1.0 mL / min.
Measurement time: 60 minutes Analysis temperature: 40 ° C
Retention time: 6- (4-aminophenyl) -1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) thieno [2,3-d] pyrimidine -2,4 (1H, 3H) -dione (7.7 min), 1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazine-3- Yl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea (14.5 min)

According to the present invention, high-quality 1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2 in high yield , 4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea or a salt thereof can be produced more safely. In addition, high quality 1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2 , 3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea or a salt thereof can be easily and efficiently produced.
Compounds (I) and (II) are prepared from 1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4- It is useful as a raw material compound for producing dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea or a salt thereof.

  This application is based on Japanese Patent Application No. 2012-217679 for which it applied in Japan, The content is altogether included in this specification.

Claims (6)

6- (4-Aminophenyl) -1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) thieno [2,3-d] pyrimidine-2, 1.6 to 2.5 equivalents of 1,1′-carbonyldiimidazole or a salt thereof , and 1,1′-carbonyldiimidazole or a salt thereof relative to 4 (1H, 3H) -dione or a salt thereof To a mixture of 1.0 to 1.5 equivalents of methoxyamine or a salt thereof , 6- (4-aminophenyl) -1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxy Pyridazin-3-yl) thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione or a salt thereof is added and reacted,
1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2,3,4- A process for producing tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea or a salt thereof. 2-[(2,6-difluorobenzyl) ethoxycarbonylamino] -4-dimethylaminomethyl-5- (4-nitrophenyl) thiophene-3-carboxylic acid or its in the presence of propylphosphonic anhydride and base Reacting a salt with 3-amino-6-methoxypyridazine or a salt thereof,
Of ethyl (2,6-difluorobenzyl)-[4-dimethylaminomethyl-3- (6-methoxypyridazin-3-ylcarbamoyl) -5- (4-nitrophenyl) thiophen-2-yl] carbamate or a salt thereof Production method. 2-[(2,6-difluorobenzyl) ethoxycarbonylamino] -4-dimethylaminomethyl-5- (4-nitrophenyl) thiophene-3-carboxylic acid or its in the presence of propylphosphonic anhydride and base Reacting a salt with 3-amino-6-methoxypyridazine or a salt thereof,
The resulting ethyl (2,6-difluorobenzyl)-[4-dimethylaminomethyl-3- (6-methoxypyridazin-3-ylcarbamoyl) -5- (4-nitrophenyl) thiophen-2-yl] carbamate or its Subjecting the salt to a cyclization reaction,
1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -6- (4-nitrophenyl) thieno [2,3-d] pyrimidine- obtained 2,4 (1H, 3H) -dione or a salt thereof is subjected to a reduction reaction,
6- (4-aminophenyl) -1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) thieno [2,3-d] pyrimidine- obtained 2,4 (1H, 3H) -dione or a salt thereof, 1,1′-carbonyldiimidazole or a salt thereof and methoxyamine or a salt thereof are reacted.
1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2,3,4- A process for producing tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea or a salt thereof. In the presence of 2,2′-azobis (2,4-dimethylvaleronitrile) and trifluoromethylbenzene, ethyl 2-[(2,6-difluorobenzyl) ethoxycarbonylamino] -4-methyl-5- (4 -Nitrophenyl) thiophene-3-carboxylate or a salt thereof and N-bromosuccinimide,
The resulting ethyl 4-bromomethyl-2-[(2,6-difluorobenzyl) ethoxycarbonylamino] -5- (4-nitrophenyl) thiophene-3-carboxylate or a salt thereof is reacted with dimethylamine or a salt thereof. ,
The resulting ethyl 2-[(2,6-difluorobenzyl) ethoxycarbonylamino] -4-dimethylaminomethyl-5- (4-nitrophenyl) thiophene-3-carboxylate is subjected to hydrolysis,
2-[(2,6-difluorobenzyl) ethoxycarbonylamino] -4-dimethylaminomethyl-5- (4-nitrophenyl) thiophene-3-carboxylic acid or a salt thereof obtained and 3-amino-6-methoxy Reacting pyridazine or a salt thereof in the presence of propylphosphonic anhydride and a base;
The resulting ethyl (2,6-difluorobenzyl)-[4-dimethylaminomethyl-3- (6-methoxypyridazin-3-ylcarbamoyl) -5- (4-nitrophenyl) thiophen-2-yl] carbamate or its Subjecting the salt to a cyclization reaction,
1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -6- (4-nitrophenyl) thieno [2,3-d] pyrimidine- obtained 2,4 (1H, 3H) -dione or a salt thereof is subjected to a reduction reaction,
6- (4-aminophenyl) -1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) thieno [2,3-d] pyrimidine- obtained 2,4 (1H, 3H) -dione or a salt thereof is reacted with 1,1′-carbonyldiimidazole or a salt thereof and methoxyamine or a salt thereof,
1- {4- [1- (2,6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2,4-dioxo-1,2,3,4- A process for producing tetrahydrothieno [2,3-d] pyrimidin-6-yl] phenyl} -3-methoxyurea or a salt thereof. Formula (I):

[Wherein, R ¹ represents a hydroxy group, a C _1-6 alkoxy group, or a C _1-6 alkoxy-pyridazinylamino group. ]
Or a salt thereof. Formula (II):

[Wherein R ² represents a nitro group . ]
Or a salt thereof.